HOXD-AS2-STAT3 feedback loop attenuates sensitivity to temozolomide in glioblastoma

AimsGlioblastoma multiforme (GBM) is the deadliest glioma and its resistance to temozolomide (TMZ) remains intractable. Long non-coding RNAs (lncRNAs) play crucial roles in that and this study aimed to investigate underlying mechanism of HOXD-AS2-affected temozolomide sensitivity in glioblastoma. MethodsWe analyzed and validated the aberrant HOXD-AS2 expression in glioma specimens. Then we explored the function of HOXD-AS2 in vivo and in vitro and a clinical case was also reviewed to examine our findings. We further performed mechanistic experiments to investigate the mechanism of HOXD-AS2 in regulating TMZ sensitivity. ResultsElevated HOXD-AS2 expression promoted progression and negatively correlated with prognosis of glioma; HOXD-AS2 attenuated temozolomide sensitivity in vitro and in vivo; The clinical case also showed that lower HOXD-AS2 sensitized glioblastoma to temozolomide; STAT3-induced HOXD-AS2 could interact with IGF2BP2 protein to form a complex and sequentially upregulate STAT3 signaling, thus forming a positive feedback loop regulating TMZ sensitivity in glioblastoma. ConclusionOur study elucidated the crucial role of the HOXD-AS2-STAT3 positive feedback loop in regulating TMZ sensitivity, suggesting that this could be provided as a potential therapeutic candidate of glioblastoma.

Automated summary

We aimed to investigate the mechanism of HOXD-AS2 in regulating temozolomide sensitivity in glioblastoma. Our results showed that elevated HOXD-AS2 expression promoted glioma progression and negatively correlated with prognosis. HOXD-AS2 attenuated temozolomide sensitivity both in vitro and in vivo, and a clinical case supported this finding. Mechanistically, we found that STAT3-induced HOXD-AS2 could interact with IGF2BP2 protein to upregulate STAT3 signaling, forming a positive feedback loop that regulates TMZ sensitivity in glioblastoma.